Reversal of Thrombin-Induced Deactivation of CD39/ATPDase in Endothelial Cells by HMG-CoA Reductase Inhibition

Kaneider, Nicole C.; Egger, Petra; Dunzendorfer, Stefan; Noris, Patrizia; Balduini, Carlo L.; Gritti, D.; Ricevuti, Giovanni; Wiedermann, Christian J.

doi:10.1161/01.atv.0000018305.95943.f7

Cited by 43 publications

(25 citation statements)

References 42 publications

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“…A suggested mechanism of action could be an improvement in CD39 activity. 39 In the present study, the use of statins was not associated with CD39 activity, but the use of statins was clearly associated with lower ADP levels. We already observed a similar phenomenon in a prospective setting in which young patients with diabetes mellitus exhibited low ADP values after statin therapy, but no change in CD39 activity.…”

Section: Discussioncontrasting

confidence: 42%

“…40 As Kaneider et al showed in an in vitro study, statins restored impaired CD39 function. 39 They did not report increased levels of expression. Thus, it could be that the beneficial effects of statins are directed to CD39 on the vascular wall and are only observed as changes in nucleotide, but not NTPDase, levels when measuring circulating values.…”

Section: Discussionmentioning

confidence: 97%

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Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Jalkanen

Yegutkin

Hollmén

et al. 2015

Circulation Research

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Rationale: Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans. Objective: The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease. Methods and Results: Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5′-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease ( P <0.0001). Low CD39 activity was associated with disease progression ( P =0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia ( P =0.001). Statin use was associated with lower ADP ( P =0.041) and tended to associate with higher CD73 ( P =0.054), while lower ATP was associated with the use of angiotensin receptor blockers ( P =0.015). Conclusions: Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y 12 receptor antagonists more than their nonsmoking peers.

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Section: Discussioncontrasting

confidence: 42%

Section: Discussionmentioning

confidence: 97%

Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Jalkanen

Yegutkin

Hollmén

et al. 2015

Circulation Research

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“…Thus, by inhibiting platelet activation through a diminished response to thrombin and by decreasing the liberation of inflammatory adenosine derivatives, the polyphenol appeared to affect oxygen free radical release and neutrophil-platelet interaction [129]. Moreover, the polyphenol protected endothelial adenosine nucleotide metabolism when downregulated by thrombin [130], preserving the suppression of endothelial CD39/ATPDase activity, which is critical in the inhibition of platelet and neutrophil activation by keeping adenosine nucleotide levels low [131]. These findings provide interesting insights into the effects of this compound on the cardiovascular system [129].…”

Section: Effects Of Resveratrol On Activation Of Different Cell Typesmentioning

confidence: 99%

Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications

Lastra

Villegas

2005

Mol. Nutr. Food Res.

626

377

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Resveratrol is a phytoalexin polyphenolic compound found in various plants, including grapes, berries, and peanuts. Multiple lines of compelling evidence indicate its beneficial effects on neurological, hepatic, and cardiovascular systems. Also one of the most striking biological activities of resveratrol soundly investigated during the late years has been its cancer-chemopreventive potential. In fact, recently it has been demonstrated that this stilbene blocks the multistep process of carcinogenesis at various stages: tumor initiation, promotion, and progression. One of the possible mechanisms for its biological activities involves downregulation of the inflammatory response through inhibition of synthesis and release of pro-inflammatory mediators, modification of eicosanoid synthesis, inhibition of activated immune cells, or inhibiting such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) via its inhibitory effects on nuclear factor (kappa)B (NF-(kappa)B) or the activator protein-1 (AP-1). More recent data provide interesting insights into the effect of this compound on the lifespan of yeast and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. It is worthy to note that the phenolic compound possesses a low bioavailability and rapid clearance from the plasma. As the positive effects of resveratrol on inflammatory response regulation may comprise relevant clinical implications, the purpose of this article is to review its strong anti-inflammatory activity and the plausible mechanisms of these effects. Also, this review is intended to provide the reader an up-date of the bioavailability and pharmacokinetics of resveratrol and its impact on lifespan.

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“…Commonly prescribed lipid lowering therapies that have salutary effects on the vasculature (e.g. HMG-CoA reductase inhibitors) and membrane phospholipids have in parallel important positive effects on endothelial cell NTPDase activity (173).…”

Section: Conclusion and Perspectivementioning

confidence: 99%

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Beldi

Enjyoji²,

Wu³

et al. 2008

Front Biosci

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Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/ CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2-expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2010 June 25. Published in final edited form as:Front Biosci. ; 13: 2588-2603. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver. KeywordsTransplantation; Liver; Purinergic Receptors; Bile; CD39; ecto-ATPase; Endothelium; Immunology; Metabolism; NTPDase; Platelet; Vasculature; Review INTRODUCTIONPurinergic signaling comprises release of extracellular nucleotides, stimulation of purinergic receptors and the modulation of nucleotide levels by ectoenzymes. Over the past decade, many advances have been made in the study of purinergic receptors and the regulation of extracellular nucleotide concentrations (1). It is now generally accepted that extracellular nucleotides (e.g. ATP, UTP, ADP), and the derivative nucleosides (e.g. adenosine from ATP), are released in a regulated manner by cells to provide the primary components for purinergic responses (2). Specific nucleo...

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Reversal of Thrombin-Induced Deactivation of CD39/ATPDase in Endothelial Cells by HMG-CoA Reductase Inhibition

Cited by 43 publications

References 42 publications

Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Aberrant Circulating Levels of Purinergic Signaling Markers Are Associated With Several Key Aspects of Peripheral Atherosclerosis and Thrombosis

Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

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